rs140486686

Positions:

• chr16-10906560-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000246.4(CIITA):​c.1068G>A​(p.Pro356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,613,160 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.90

Genes affected

CIITA (HGNC:7067): (class II major histocompatibility complex transactivator) This gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein is located in the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the "master control factor" for the expression of these genes. The protein also binds GTP and uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus it does not bind DNA but rather uses an intrinsic acetyltransferase (AT) activity to act in a coactivator-like fashion. Mutations in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-10906560-G-A is Benign according to our data. Variant chr16-10906560-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr16-10906560-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000821 (125/152328) while in subpopulation NFE AF= 0.00119 (81/68026). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.1068G>A	p.Pro356=	synonymous_variant	11/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.1068G>A	p.Pro356=	synonymous_variant	11/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000858 AC: 215 AN: 250630 Hom.: 2 AF XY: 0.000877 AC XY: 119 AN XY: 135676

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00102 AC: 1484 AN: 1460832 Hom.: 4 Cov.: 31 AF XY: 0.00104 AC XY: 758 AN XY: 726716

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74492

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000858

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MHC class II deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 30, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

CIITA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

CIITA: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.51
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140486686; hg19: chr16-11000417;